Thrombomodulin (TM) was originally identified as an anti-coagulant factor that activates protein C. Recent reports suggest that TM is involved in biological processes including cell-cell adhesion, epithelial-mesenchymal transition, and inflammation in addition to haemostasis. TM comprises a C-type lectin-like domain (domain 1, D1), a domain with six epidermal growth factor (EGF)-like structures (domain 2, D2), as serine/threonine-rich domain (domain 3, D3), a transmembrane domain (domain 4, D4), and a cytoplasmic domain (domain 5, D5). Soluble forms of TM are reported high in the plasma of septic patients. Because TM is a natural anti-coagulant protein, recombinant human soluble TM protein (ART-123) effectively reduces disseminated intravascular coagulation.
Furthermore, recombinant TM lectin-like domain (rTMD1) suppresses lipopolysaccharide (LPS)-induced inflammation by binding directly to LPS and high-mobility group box 1 protein. Although the anti-inflammatory activity or activated protein C (APC) has been demonstrated, the pulmonary immune responses to respiratory pathogens and LPS in mice with strongly reduced protein C activation (TMpro/pro mice) are not different from those in wild-type mice, suggesting that TM can modulate host inflammatory response through a protein C-independent mechanism.
CD14, a glycophosphatidylinositol-anchored membrane protein, is a receptor for LPS. It transfers LPS to the Toll-like receptor (TLR) 4/myeloid differentiation factor-2 complex and elicits downstream signaling pathways, including the mitogen-activated protein kinase, nuclear factor-κB, and interferon regulatory factor 3 pathways, resulting in the production of pro-inflammatory cytokines and type I interferons. Recent studies have reported that CD14 is involved in the activation of TLR2, TLR3, TLR7, and TLR9, since CD14-deficeint macrophages and dendritic cells display reduced inflammatory response to the specific ligands of these TLRs. Soluble forms of CD14 have also been detected in circulating blood and facilitate LPS-induced inflammatory response in endothelial and epithelial cells that do not express the membrane form of CD14. These results suggest that CD14 is a critical pattern-recognition receptor in the innate immunity against a broad spectrum of ligands. Accumulating evidence indicates that CD14 contributes to pathological conditions, including sepsis, liver fibrosis, metabolic syndrome, Alzheimer's disease, and neuropathic pain. Mice with CD14 deficiency are resistant to endotoxin shock and reduce dissemination of Gram-negative bacteria. In an experimental cholestasis model, mice with CD14 deletion display reduced liver fibrosis resulting from a decrease in the production of tumor necrosis factor-α (TNF-α) and transforming growth factor-β. Endotoxemia-initiated obesity and insulin resistance can be attenuated by knocking out CD14 in mice. CD14 knockout mice also exhibit a reduced deposition of β-amyloid plaque in the brain via changes in the brain inflammatory environment. In a neuropathic pain model (spinal nerve L5 transection), knockout of CD14 in mice suppresses mechanical allodynia and thermal hyperalgesia. Increased mechanical hypersensitivity in mice is observed after intrathecal injection of soluble CD14. According to these reports, targeting CD14 may be a potential therapeutic strategy in CD14-related diseases.